Anorexia is a common problem of neoplastic disease that limits aggressive therapy of cancer and increases the morbidity and mortality of the disease. Although many hypotheses of cancer anorexia have been advanced, the complexity of physiologic controls of feeding and satiety have precluded resolution of this problem. Since cancer anorexia appears to be due to remote effects of a tumor that are disseminated humorally, any integrative theory must consider the interaction of peripheral biochemical aberrations with brain mechanisms of feeding and satiety. Results from studies of experimental cancer suggest that large quantities of glucose and amino acids are removed from circulating blood by the tumor mass. The amino acid, glutamine, appears to be particularly important for tumor metabolism, since blockade of glutamine metabolism effectively reduced tumor growth. The major products of tumor metabolism appear to be lactic acid and ammonia. Recent studies demonstrated a 3-fold elevation in blood ammonia concentration in anorectic tumor- bearing (TB) rats and a 10-fold increase in ammonia concentration in blood draining the tumor mass. Ammonia intoxication produces anorexia and elevations in brain glutamine, large neutral amino acids and amine neurotransmitters that are similar to changes observed in anorectic TB rats. Therefore it is hypothesized that the increased ammonia concentrations in the blood and brain and the neurochemical aberrations induced by the detoxification of ammonia in the brain area very important factors in the development of cancer anorexia. This hypothesis will be tested by: (1) determining the temporal relationship between alterations in blood and brain ammonia on the onset of anorexia in TB rats; (2) assessing the effects of ammonia infusions in normal rats on food intake and neurochemistry; (3) measuring the increase in CSF glutamine as anorexia develops using intraventricular push-pull perfusion of TB rats; (4) assessing the anorectic effects in the intraventicular adminstration of glutamine to normal rats; (5) determining the effects of a glutamine synthetase inhibitor on cancer anorexia; (6) assessing whether infusion of arginine and citrulline will aid in host detoxificiation of ammonia and reduce the anorexia; (7) exploring dietary changes that reduce glutamine and the increased neutral amino acid concentrations in the brain as treatments for anorexia; and (8) determining whether blood ammonia concentrations are elevated in anorectic cancer patients. These experiments should delineate specific causes of anorexia in cancer and suggest several therapeutic options.